HSP90-CDC37 functions as a chaperone for the oncogenic FGFR3-TACC3 fusion

The FGFR3-TACC3 (F3-T3) fusion gene was discovered as an oncogenic molecule in glioblastoma and bladder cancers, and has subsequently been found in many cancer types. Notably, F3-T3 was found to be highly expressed in both untreated and matched recurrence glioblastoma under the concurrent radiotherapy and temozolomide (TMZ) treatment, suggesting that targeting F3-T3 is a valid strategy for treatment. Here, we show that the F3-T3 protein isa client of heat shock protein 90 (HSP90), forming a ternary complex with the cell division cycle 37 (CDC37). Deprivation of HSP90 or CDC37 disrupts the formation of the ternary complex, which destabilizes glycosylated F3-T3, and thereby suppresses F3-T3 oncogenic activity. Gliomas harboring F3-T3 are resistant to TMZ chemo-therapy. HSP90 inhibitors sensitized F3-T3 glioma cells to TMZ via the inhibition of F3-T3 activation and potentiated TMZ-induced DNA damage. These results demonstrate that F3-T3 oncogenic function is dependent on the HSP90 chap-erone system and suggests a new clinical option for targeting this genetic aberration in cancer.

Automated summary

The FGFR3-TACC3 fusion gene is highly expressed in various cancers and affects the treatment of glioblastoma. Its activity is dependent on heat shock protein 90 and cell division cycle 37, and inhibition of these proteins can suppress its oncogenic function. Additionally, HSP90 inhibitors can enhance the sensitivity of glioma cells with this fusion gene to chemotherapy.